Preliminary safety data from a randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4125-4125 ◽  
Author(s):  
Matthew H. G. Katz ◽  
Gauri R. Varadhachary ◽  
Todd W. Bauer ◽  
Nicolas Acquavella ◽  
Nipun B. Merchant ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Neoadjuvant Treatment ◽  
Safety Data ◽  
Neoadjuvant Chemoradiation ◽  
Resectable Pancreatic Cancer ◽  
Borderline Resectable ◽  
Resectable Disease ◽  
Post Surgery ◽  
Grade 3 ◽  
To Receive

4125 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy.Tumor-infiltrating lymphocytes (TILs) do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of TILs in the PC microenvironment. We hypothesized that combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC have been randomized 2:1 to the investigational treatment (Arm A) to receive pembrolizumab 200mg IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday-Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. Restaging CT scan or MRI is performed at 4-6 weeks after completion of neoadjuvant treatment, and patients with resectable disease will undergo surgical resection. Here we report the preliminary safety data based on 22 enrolled patients. Results: As of February 3-2017,22 patients have been enrolled (14 Arm A and 8 Arm B). 50% of the patients had resectable disease (7 arm A; 4 arm B) and the other 50% had borderline resectable disease (7 Arm A; 4 arm B). Post-neoadjuvant therapy, 6 patients had unresectable disease (3 on each arm), and 14 patients underwent surgery (10 arm A and 4 arm B). There were 7 grade 3 treatment-related toxicities in Arm A (5 patients): 2 grade 3 diarrhea attributed to CRT; 4 grade 3 lymphopenias attributed to pembrolizumab, CRT or the combination; and one patient had elevated alkaline phosphatase probably related to the combination that met the definition of DLT and resolved after holding the treatment and receiving steroids. There was only one grade 3 toxicity on Arm B: lymphopenia attributed to CRT. No grade 4 toxicities have been reported on either arm. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizuamb is safe based on the presented data. Clinical trial information: NCT02305186.

Randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4128-4128
Author(s):  
Osama E. Rahma ◽  
Matthew H. G. Katz ◽  
Brian M. Wolpin ◽  
Andressa Dias-Costa ◽  
Jonathan Nowak ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Standard Of Care ◽  
Neoadjuvant Chemoradiation ◽  
Resectable Pancreatic Cancer ◽  
Borderline Resectable ◽  
Post Surgery

4128 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy due to suppressive immune-microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of tumor-infiltrating lymphocytes (TILs). We hypothesized that the combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC were randomized 2:1 to the investigational treatment (Arm A) of pembrolizumab 200mg IV every 3 weeks concurrently with CRT (capecitabine 825 mg/m2 orally twice daily and radiation 50.4 Gy in 28 fractions over 28 days) or CRT only (Arm B) prior to surgical resection. The primary endpoints were treatment safety and density of TILs with the objective to estimate differences in TILs density between the investigational and the control arms. Immune cell densities were assessed using multiplexed immunofluorescence on resected tumor specimens. Densities of CD8+TILs were measured in 2-10 representative regions containing residual cancer per case and then averaged to obtain overall densities. The study was amended after enrollment of 37 patients to allow FOLFIRINOX prior to CRT, given changes in standard of care. Results: 37 patients were enrolled (24 Arm A and 13 Arm B). Post-neoadjuvant therapy, 13 patients had unresectable disease (9 on A and 4 on B), and 24 patients underwent surgery and were evaluable for the TILs primary endpoint (17 arm A and 7 arm B). The mean difference (A-B) in CD8+ cell density was 36 cells/mm2 (95% CI -85 to 157, stdev 130) (p 0.48). Additional analysis did not show significant differences in CD8+Ki67+ (activated cytotoxic T-cells), CD4+, and CD4+FOXP3+ (regulatory T cells), M1- or M2-like polarized macrophages, or granulocytes. The median recurrence free survival (RFS) was 18.2 months on Arm A and 14.1 on Arm B (p 0.41) and Overall Survival was 27.8 months on Arm A and 24.3 on Arm B (p 0.68) with a median follow up of 2.2 years. The most common grade 3 treatment-related toxicities were lymphopenia reported in 29% on Arm A and 31% on Arm B followed by diarrhea in 8% on Arm A attributed to CRT. There was only 1 DLT of increased ALT attributed to the combination on Arm A that resolved after holding the treatment and receiving steroids. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizumab is safe. Preliminary analysis shows that the addition of pembrolizumab to CRT has minimal effects on several immune cell populations including CD8+TILs in the PC microenvironment. The study is currently enrolling 25 more patients who receive FOLFIRINOX prior to randomization to CRT+/- Pembrolizumab, which will help to dissect the immune modulatory effect of chemotherapy followed by CRT. Clinical trial information: NCT02305186.

Margin status and neoadjuvant chemoradiation in patients with borderline resectable pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 304-304
Author(s):  
Pavlos Papavasiliou ◽  
Jonathan R Piposar ◽  
Rodrigo Arrangoiz ◽  
Kathryn T Chen ◽  
Fang Zhu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Disease Free Survival ◽  
Positive Margin ◽  
Neoadjuvant Chemoradiation ◽  
Margin Status ◽  
Negative Margin ◽  
Resectable Pancreatic Cancer ◽  
Consensus Definition ◽  
Borderline Resectable ◽  
Positive Margins

304 Background: The objective of this study was to examine the effect of margin status and neoadjuvant therapy in determining outcomes for borderline resectable (BLR) pancreatic cancer and how neoadjuvant chemoradiation impacts margin of resection. Methods: A retrospective chart review was conducted to identify patients who underwent resection for BLR pancreatic cancer based on the AHPBA/SSO/SSAT consensus definition. Outcomes including overall survival (OS) and disease free survival (DFS) were determined based on margin status, location of positive margin (artery, vein, or pancreas), and receipt of neoadjuvant chemoradiation. Results: One hundred and three patients who met the definition of BLR pancreatic cancer and underwent resection between April 1993 and July 2010 were reviewed. Mean age at diagnosis was 65 with a median follow up time of 19.7 months. Neoadjuvant chemoradiation was administered in 49.5% of patients. Twenty-five percent of patients underwent portal and/or superior mesenteric vein resection, and 7% hepatic artery resection. Microscopic positive margin rate was 54%. Median OS was 17.2 months for patients with positive margins versus 24.9 months for patients with negative margins (p=0.003). Median DFS was 13.1 months for patients with positive margins versus 18.6 months for patients with negative margins (p=0.001). There was no difference in OS or DFS for patients with positive margins based on location or number of positive margins. Of the patients who received neoadjuvant chemoradiation, 61.7% had a negative margin of resection versus a 38.3% negative margin of resection rate for patients who did not receive neoadjuvant chemoradiation (p=0.02). Among patients with a positive margin, there was no difference in OS or DFS with or without neoadjuvant chemoradiation. Conclusions: A positive margin of resection, irrespective of location or number, is associated with worse outcome in patients with BLR pancreatic cancer. The use of neoadjuvant chemoradiation is associated with higher rates of margin free resection.

Accelerated fraction radiotherapy with concomitant capecitabine as neoadjuvant therapy of borderline resectable pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 329-329 ◽  
Author(s):  
Samhita Chakraborty ◽  
Todd W. Bauer ◽  
Monica M Morris ◽  
Erin Yarde ◽  
J Thomas Parsons ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Mechanisms ◽  
Palliative Therapy ◽  
External Beam Radiation ◽  
Resectable Pancreatic Cancer ◽  
Borderline Resectable ◽  
Beam Radiation ◽  
Early Stage Disease ◽  
Borderline Resectable Pancreatic Cancer ◽  
Grade 3

329 Background: Surgical therapy remains the only curative modality for pancreatic cancer, though survival remains quite poor even for patients with resected early stage disease. Better (neo) adjuvant therapies are needed to improve resectability rates for patients with borderline resectable pancreatic cancer and to prevent recurrence following resection. We undertook this pilot study to determine the safety of accelerated fraction radiotherapy (AFRT) with capecitabine in such patients. Methods: Eligible patients have histologically confirmed borderline resectable adenocarcinoma of the pancreas as defined by the MD Anderson categories of vascular involvement, indeterminate metastatic disease, borderline performance status; normal organ function; and no prior therapy for pancreatic cancer. Radiation is given as external beam radiation therapy to a dose of 50 Gy delivered in 20, 2.5 Gy fractions Mon-Fri using IMRT. If insurance denied IMRT, 3D conformal techniques with daily image guidance is permitted. Capecitabine is delivered as 825mg/m2 BID on radiation days. The primary outcome is to determine the frequency of treatment-related adverse events (AE). Planned enrollment is 40 pts. Results: 10 pts have enrolled to date. 8/10 received IMRT. This regimen has been exceedingly tolerable. Lymphopenia is the most common AE (n=10), grade 3-4 n=6. Other common toxicities were hyponatremia (n=6), fatigue (n=5). Grade 3 AE occurred in 8 pts, grade 4 in 3 patients. One pt had hemorrhage from a radiation induced gastric ulcer complicated by an MI. 5/10 pts had stable disease and were resected and 4/5 had an R0 resection. In the remaining 5/10 patients, disease progressed outside the pancreas and they are receiving palliative therapy. Conclusions: The combination of AFRT and capecitabine was well tolerated. Xenograft models derived from these patients’ tumors are being used to study molecular mechanisms of treatment resistance that could be targeted in a follow up phase II study building on this platform.

NEONAX trial: Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer, a phase II study of the AIO pancreatic cancer group (AIO-PAK-0313)—Safety interim analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4128-4128 ◽  
Author(s):  
Waldemar Uhl ◽  
Thomas Jens Ettrich ◽  
Anke C. Reinacher-Schick ◽  
Hana Algül ◽  
Helmut Friess ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Phase Ii Study ◽  
Neoadjuvant Treatment ◽  
Postoperative Mortality ◽  
Preoperative Imaging ◽  
Resectable Pancreatic Cancer ◽  
Perioperative Treatment ◽  
Grade 3

4128 Background: Survival in pancreatic cancer (PDAC) is still poor even after curatively intended resection. Perioperative treatment approaches improve outcome in various tumor entities. Data on perioperative treatment in resectable PDAC are limited and there is a debate whether neoadjuvant treatment might impair subsequent surgery by adding perioperative morbidity or mortality. Methods: NEONAX is a randomized phase II study (planned 166 patients) of perioperative gemcitabine/nab-paclitaxel (Arm A: 2 pre- and 4 post-operative cycles, Arm B: 6 cycles adjuvant) for patients with primarily resectable PDAC. Primary objective is DFS at 18 months after randomization. Secondary objectives are 3-year OS-rate and DFS-rate, progression during neoadjuvant therapy, R0/R1 resection rate and QoL. Results: NEONAX was initiated in March 2015 in 26 centers for PDAC surgery in Germany. The data represent the safety interim analysis (IA) of the first 48 patients. 25 patients were randomized to Arm A and 23 to Arm B. Patients’ median age was 65.3 years (56.3% males, 43.8% females, 85.4% ECOG 0). Out of 25 patients in Arm A 20 patients (80%) underwent surgery, compared to 21 of 23 patients (91.3%) in Arm B with upfront surgery. Reasons for no resection were intraoperatively determined small liver metastases (2 cases, Arm A), withdrawal of informed consent (2 cases in each arm) and 1 patient with uncontrolled cholestasis (arm A). Postoperative complications occurred in 45% of arm A and 42.8% of arm B. (pancreatic fistula: 15% in arm A and 9.5% in arm B, infections: 10% in arm A and 9.5% in arm B) All resected patients were alive 60 days after surgery. At least 1 adverse event (AE) NCI-CTCAE ≥ grade 3 occurred in 60% of the perioperative and 39.1% of adjuvant treatment arm. Most common AEs were neutropenia (16.7%), fatigue (10.4%) and infections (10.4%). Conclusions: There was an increase in NCI-CTCAE ≥ grade 3 events in the perioperative arm, but this was manageable and did not result in increased peri- or postoperative mortality. 8% of patients in the perioperative arm did not get resected due metastases detectable during surgery, but not on preoperative imaging immediately prior to surgery. Therefore, it cannot be determined whether these metastases were preexistent or developed during neoadjuvant treatment. In conclusion, the first interim analysis of the NEONAX trial shows that this protocol can be safely applied to patients with resectable PDAC in a perioperative setting. Clinical trial information: NCT02047513.

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